N-naphthyl maleamic esters



Patented Dec. 22, 1953 N-NAPHTHYL MALEAMIC ESTERS Waldo B. Ligett,Berkley, Calvin N. Wolf, Ferndale, and Rex D. Closson, Detroit, Mich.',assignors to Ethyl Corporation, New York, N. Y., a corporation ofDelaware No Drawing. Application April 30, 1951, Serial No. 223,824

11 Claims.

This invention relates to novel maleamlc esters. In particular ourinvention relates to the esters of maleamic acid wherein the amidenitrogen is substituted with a naphthyl radical, thereby providing aclass of compounds possessing unusual fungitoxic properties. Ourinvention also relates to methods of formulating such compounds intouseful fungicides and methods for their application.

Various maleamic acids have been produced and disclosed in the prior artwherein the nitrogen of the amide group has been substituted with avariety of organic radicals and wherein various inorganic radicals havereplaced one or more of the hydrogen atoms of the unsaturated linkage.Various acid derivatives such as, for example, the metal salts and theorganic salts have likewise been prepared in this series. However, theseacid derivatives do not possess inherent toxicity to fungus organisms,although certain of such materials have shown limited utility in thegeneral field of pesticidal activity.

It is an object of our invention, therefore, to provide derivatives ofmaleamic acids which have high utility in the protection of a widevariety of materials from fungusattaok. It is a further object of ourinvention to provide a class of materials which provide protectionagainst a diversity of fungus organisms. It is also an object of ourinvention to provide a novel class of chemical compounds.

The compounds of our invention comprise the N-naphthyl maleamic acidesters which can be illustrated by the following general formula:

We have made the discovery'that by esterifying the carboxylic acid groupof N-naphthyl male covery is more surprising in view of the fact that Ithe free acids or salts thereof possess a wider range of solubilities inaqueous solvents than the esters of our invention. However, we havefound that in an aqueous system our esters are effective whereas theacids and salt-like derivatives of the 2 acids are ineffective or ofextremely limited effec-' tiveness.

In the above general formula for the com-. pounds of our invention weobtain the effective characteristics of our novel fungitoxicants whenthe group R is alkyl, or a derivative thereof such as, for example,aralkyl, alkenyl and various substitution products thereof, for example,the halogen-, sulfur-, or nitrogen-substituted derivatives. We havefound our novel class of compounds retain and in some instancesexhibitenhanced activity when, the X and Y of .the above general formulaare the same or different and are chosen from hydrogen, the halogens,sulfhydryl, amino, substituted amino, nitro and nitroso radicals. In thesimplest embodiments of our invention we prefer the naphthyl group to beunsubstituted. However, we have found that considerable activity isexhibited by the derivatives whereinthe naphthyl radical is substitutedwith one or more chlorine, amino, nitro or alkyl groups, or acombination thereof.

The choice of the various substituents X, Y, R and the naphthylsubstituents depends largely on the type of material being protected byour fungitoxicants, the method of application which is selected and to alesser degree the particular fungus organisms against which protectionis sought. For example, such considerations as solubility, volatility,phytotoxicity, animal toxicity, compatibility with inert carriers,weatheringcharacteristics, staining characteristics of the activeingredient, as well as similar properties of the compositions in whichthese materials are formulated, and in addition the pour point,

fluidity, appearance, etc., all must be considered;

in choosing a fungicide for commercial application. Thus, provided withthe fungitoxic grouping which we have discoveredas in the above generalformula it is possible to tailor our basicstructure to provide s,variety of fungitoxicants,

each of which has merit for some combination of properties or level oftoxicity and is particularly suited to solvethe problem at hand.

The following examples of specific embodiments of the compounds of ourinvention serve to illustratemethods which we employ for manufacturingour materials and will indicate the chemical and physical properties ofour novel class of compounds. However, we do not intend thatour'invention be limited by the specific illus-' trations herein asother embodiments are clearly within the scope of our invention andother methods for their manufacture will be apparent to those skilled inthe art. In the examples 3 which follow all parts and percentages are byweight.

EXAlVIPLE I of to minutes, the product wascollecteidf by filtration anddried. "The yield of yellow crystals was 90 parts, corresponding to ayield of 99 per cent. This product melted at 1 38- -& 0 In a reactionvessel equipped with a refluxc'on denser were placed 100 parts of thisarnaphthyh maleamic acid, 400 parts of methanol, and 5 parts of,p-toluene-sulfonic acid monohydrate. This mixture was boiled underreflux for a period of. hours,- cooled to a temperature of about (1..and added to 300" parts of a 3. per cent aqueous. sodiumbicarbonate'solution, After stir.- ring, for 1D.- minut'es, the solid product wascollected by filtration, washed with water, and" dried. The. yield of;crude product was 95- parts; cor responding. to a yield of 89 per cent;Recrystal lizationnfrom. methanol. gave 64 parts: of white" needles,melting, atv 126-1277 0.1 This. material contai'ned7025per. centicarbon511 per cent by d'rogen, and-.513 percent nitrogen while the for= mul'aCisHmCaN' requires 70.6 per cent carbon, 511' per cent, hydrogen and 5.5per cent nitrogen;

' Ethyl ester of N-(a-naplitiiylimaleamz'c' acid.Using the same processdescribed in Ex-- ample I, 72.3parts of N'- fie-naphthyll ma-leamicacid" was treated with 4000'- parts of anhydrous" ethanol in thepresence of a' catalytic amount of p-toluenesulfonic acid. Theyield-ofcrude-product was5'75" parts; corresponding to a yield'of '71per cent. After recrystallizationf-rom ethanol, the ethyl ester wasobtained as colorless needles, melting" at a temperature of 1H5to=120'''.

acidZ-B'ythe procedure of" Example I fi-(a p c'hloroethylz ester oiN-(aenaphthyl)? maleamic': acidp-T'ou a2. reaction: vesselequipped. withar-refiuxicondenser, meanszforrstratifyingtheme-- the' condensed fluxliquid; means forremoving;

organicv liquid water and returning. the upper.- p liase as. recycletor: the reactor;

parta of ethylenechlorohydrin, ISQ-parts of. 10111-1-ene;,and.5=parts.of. p -toluenesulfonic acid. The. mixturefwas heatedat, reflux.

were.- added. 7.0.- parts; of. Ni-lw-naphthylir maleamic. acid, 20.0.-

temperature for. a. periodofl 15 hours, at.which .time-. the removal.

of water formed in the reaction was substantially complete. The majorportion of the toluene and excess ethylene chlorohydrin was removed bydistillation, and the crude product was washed with bicarbonate of sodasolution and purified essentially as; described. in Example. I.

EXAMPLE V B-Nitro-n-butyl ester of N-(a-naphthyl) maleamicacid.Following the procedure of Example IV; zl-nitrobutanol-l wastreated with N-(anaphthyl) maleamic acid and p-toluenesulfonic acid; in.toluene. The product, the c-nitro-nbutyl. ester. of Nf-(a-naphthyl)maleamic acid,

, was recovered as, in the preceding example and purified as in ExampleI.

(Dther'typical esters of N-(emaphthyI) maleami'c' acid include thep-trichloroethyl, B-(N,N- dimethylamino) ethyl, p-ethoxyethyl,p-bromoethyl, p-chlorobenzyl, 2,4-dinitrobenzyl, 42,4- dichlorophenoxy)ethyl, and 2-propenyl esters which we. prepare as in the foregoingexample by employing, as theesterifying alcohol filfiifitrfchlbroethanol; N;N"-dimethyl ethanolam'ine, the monoethyl ether" ofethylene glycol, ethylene bromohydrin, p chlorobenzyl alcohol; ZA-d'ini'trobenzyl alcohol; 2,4-dichlorophenoxy ethanolandallyl'. alcohol,respectively.

EXAMPLE VI Methyl ester ofa-chZoro N-("a-naphthyl)maleami'cacid.--a-hloro-N -(kz-naphthyl y malhami'c? acid was preparedby treatingichloromaleicf arrhydride with" e-naphthylamineby theprocedure describedin Example I for the preparation: of N-(a-naphthyl)*maleamic acidi A solution. of the sodium salt was prepared: by treating4822* parts of this a-chIoro'-N--(w-naphthyl)' maleamicf acidwith 8parts of sodium hydroxide dissolved in- 250 partsof water; This-solutionwas? cooled. t'oa temperature of 0" to 5- C. and added to astirredcool'ed' solution of 3-4" parts of silver his trate in parts ofwater. Stirring was" conti'nued for" 10 minutes;- during which periodthe silver salt ofw-chloro-N -(@naphthyl) m'aleannc acid' separated andwas then recovered by'filtratti'on, washed with cold water and withethanol; and then dried. The dry silver salt was sus=-- pended in- 250parts ofanhydrous ether? in a re? action vessel equipped with anagitator, and. 14.2? parts-- of methyl iodide was added in small pertions to this suspension over a period of 15min? utes. Themixture wasthen stirred at 20 -259 C. for anadditional period of twohours, and theprecipitated silver iodide was removed by filtration. The ether solutionwas extracted with 5 per cent aqueous sodium bicarbonate solution andthen with water. After" drying in the presence of anhydrouscalciumsulfate, the ether and excess. methyl iodide were removed bydistillation. at. reduced. pressure; The product separated as. a.residue and Was crystallized from ether, yielding 40; parts of whitecrystalline product which. melted. at 83-85? 0., corresponding to ayield of 783 percent.

vr-B'ntyl' ester Of N-(a-naphfliyl) a'-Cli rG7'0"-- mcleamz'eacid.-Using essentially" the procedure of Example VI; 6816' parts of thesilversalt' or achl'oro-N- (a naphthyl) maleami'cacid was" treated with18 parts ofn-butyl iodide. After'crys tallization from hexane, the"yield of crystalline product-was 2'4 parts; meltingata' temperatureof' a31-35? Cl In accordance with the foregoing description of thepreparation of esters of N-(a-naphthyl) maleamic acid, the correspondingtypical esters of a-chloroN-(a-naphthy1) maleamic acid can be similarlyprepared by esterifying this acid with the appropriate alcohol.

Furthermore, esters of other naphthyl maleamic acids can be prepared inaccordance with our invention. For example, by any of the foregoingprocesses we can prepare esters of B-chloro- N-(a-naphthyl) maleamicacid, a-ChlOlO-N-(B- naphthyl) maleamic acid, a, 3-dibromo-N-(naphthyl)maleamic acid, a-amino-N-(a-naphthyl) maleamic acid, a-(N,N-dimethylamino) -N- (anaphthyl) maleamic acid, naphthyllmaleamicacid, a-nitroso-p-chloro-N- (a-naphthyl) maleamic acid,a-l'litI'O-N-(a-Ilaphthyl) maleamic acid, N-(fi-naphthyl) maleamic acid,N-(1,4-dichloro-2-naphthyl) maleamic acid,a-chloro-N-(B-nitro-a-naphthyl) maleamic acid, N-(B-methyl-a-naphthyl)maleamic acid, a,,B-dlbromo-N-(,e-chloro-a-naphthyl) maleamic acid,a-sulfhydryl-N-(a-ethyl-B-naphthyl) maleamio acid and N-(a-naphthyl)citraconamic acid. Many other variations of the compounds of ourinvention will be apparent to those skilled in the art.

The compounds of our invention can be employed as fungicides and for theprevention of the germination of the spores of fungi. One method ofapplying our fungicides is in the form of a Water suspension, wherein asurfac active agent has been incorporated in suflicient amount todisperse and suspend the fungicide. Examples of such surface activeagents which can be employed in forming dispersions include salts of thealkyl and alkylaryl sulfonates, such as Du Pont MP-189 and Nacconol-NR,alkyl sulfates, such as Dreft, alkylamide sulfonates, such as Igepon-T,the alkylaryl polyether alcohols, such as Triton X-100, the fatty acidesters of polyhydric alcohols, such as Span, the ethylene oxide additionproducts of such esters, as for example Tween, and the addition productsof long-chain mercaptans and ethylene oxide, such as SharplesNon-Ionic-2l8. Still other surface active agents can be employed, theabove merely showing a representative list of the more common materials.

The solubility of our N-(naphthyl) maleamic acid esters in organicsolvents, furthermore, is such that they can be applied advantageouslyin the form of solutions in this type of solvent, and for certainapplications this method of application is preferred. For example, intreating cloth, leather or other fibrous articles it may be desirable toapply our fungicides dissolved in a volatile solvent. After use thevolatile solvent evaporates leaving the fungicide impregnated throughoutthe surface of the article. Likewise, in applying our fungicides tosmooth surfaces, as for example in treating wood surfaces for protectionagainst fungus attack, a solution may be the most practical method forapplying a protective film by brushing, spraying or dipping. The choiceof an appropriate solvent is determined largely by the concentration ofactive ingredient which it is desired to employ, by the volatilityrequired in a solvent, the spreading or flow characteristics thereof,and by the nature of the material being treated. Among the many organicsolvents which can b employed as the carrier for our fungicides we canemploy hydrocarbons, such as benzene or toluene; ketones, such asacetone and methylethyl ketone; chlorinated solvents, such as carbontetrachloride, trichloroall and perchloro-ethylene and esters, such asethyl, butyl and amyl acetates; and alcohols, such as ethanol,isopropanol, and amyl alcohols. Among the solvents which we prefer toemploy are the Carbitols and Cellosolves, the former comprising ingeneral the monoalkyl ethers of diethylene glycol and the latter themonoalkyl ethers of ethylene glycol. In addition, combinations of thesevarious typical solvents can be employed whereby special volatility andviscosity characteristics can be imparted to our formulations.

In addition to the above-described methods of wet application of theesters of N-(naphthyl) maleamic acid we can prepare compositions inwhich our materials are extended in talc, clay or other solid diluents.Such formulations have particular utility in the treatment of seeds,wherein an aqueous application may promote premature germination, orwhere a solvent application may damage the seed. For certain field cropapplications we also prefer a. dust formulation wherein a Wetapplication might introduce certain secondary effects which areundesirable. specific examples of such typical inert solid carrierswhich can be employed as diluents in our dust formulations includefullers earth, Pyrophillite, Attaclay and the Fi-ltrols.

To demonstrate the utility of our N-(naphthyl) maleamic esters asfungicides we determined the concentration at which the germination of50 per cent of the spores of each'oi the fungi Alternaria oleracca andSclerotinia fructicola is inhibited. The former is responsible for thepotato blight, while the latter causes peach rot. These fungi arerepresentative of fungus types which are re sponsible for heavy cropdamage. The ability to control these fungi is a reliable indication ofthe general applicability of our fungicides to protect importantagriculturalcrops. These tests were conducted as follows: 100 parts ofthe active ingredient was triturated with 1,000 parts of distilled watercontaining one part of the commercial dispersant Triton X-lOO. Thisstandard suspension was thereupon further diluted with distilled waterand the concentration at which one-half of the fungi contained in a dropof water on a.

microscope slide were prevented from sporulating was determined. Thisstandard slide-germination method is described and Committee onStandardization of Fungicidal Tests of the American Phytopathologic alSociety in Phytopathology, 33, 627' (1943). In the following table arelisted typical results of thesedeterminations and differentiates betweenour esters and the salt derivatives of the corresponding acids.

Further demonstration of the utility of our compounds as fungicides hasbeen shown in a more specific manner by determining the minimum amountof the active ingredient required to prevent the sporulation of per centof the Further accepted by the C 11 cent rat io 11 (p. p. m.) to inhibitsporulation 95 per- Oompound" cent S fructicola olcmcea ll/l'thyliester. of a-cbloro-N-(a-naphthyl) maleamic acid l1 8 n-Butyl ester' of,u-ch1bl0'-N'-(a-naphthyl) maleamio acid. ll 11' Copnersuliatc (Standard)V 19.

Of, particular importance in the treatment. of. agricultural: cropsagainst fungus diseases is the susceptibility of; the plant to.- damageby the fun gitoxicant employed. Our materials. are particularly;advantageous. in this respect, since in a; variety of tests we havefound-.110 evidence that our materials are toxic toplants or inhibit inway-the. normal. functioning of the plantar the germination-of seeds. Wehave demonstrated the. innocuous nature; of: our iungitoX-icants bydipping theentirezleafof. each of corn, soybean, tomato; cucumber. andcotton. plants in. suspension's. of. our fungicides. at concentrationsas high 3 .10.000.12. p..m.v and. have-observed. no effect on thesix-treated plants or. upon. the leaves which v One-third; of. these.infected plants weresprayed Q witha- 0.2. per cent aqueous suspension ofatypical. fungicide of, our invention, the.- n-butylester of.a.-chloro-N.--(m-naphthyl) maleamic. acid, onethird were sprayed in. alike mannenwith a. 0.2

per. cent. aqueous suspension.v of} the commercial fungicide, zincdimethyl dithiocarbama-teand one-third were left as controls. At thetermination of the demonstration, after the full efiect of 8 fungus hadbeen. produced,. the: plantssprayed with. the: n-butyl ester ofa-chloro-N-(e-naphrthyl), maleamic acid. had. developed only per: centof the number. of disease: lesions developed by the controls, while theplants sprayed. with zinc dimethyl dithiocarbama-te: had 31 per cent asmany lesions as'the control plants. Thus, essentially complete controlof Tomato Early Blight. was obtained by our material under conditions;

wherein a commercial. fnngitoxicant was of only' limited efi-ectiveness.

Having described various embodiments of the novel compounds of. ourinvention and pointed out the utility to which they may be. applied. donot intend thatv our; invention should be: lime ited. to the. abovespecific examples; of our com-' pounds. or methods of their applicationor use except as-in the appended'claims;

We claim:

1. The lower alkyl esters of N-naphthylma leamic acid.

2.. As new compositions. of matter, lower altphatic esters of N-naphthylmaleamicracids.

3.. As anew compositionaoimatter, methyl-N e-na-phthyl) -maleamate;.

e. Fungicidal compositions. consisting. essen tially of lower aliphaticesters of N-naphthyl:

maleamic acids together with. an. extender- 5. Ethyl ester ofN--(-naphthyl)-= maleamitr acid.

6. n-Butyl ester of N-(a-naphthyl) malcamicr acid.

References Cited in; the. file ofthis patent Hurd etv al; J. Org. Che,vol. 2 (1937), pp.

Anschultz: Liebigs Ann vol. 461 (1928), pp: -91;

Parola et al.: Gazz chim. itall, vol 64 (1934*); pp'.919 -31'.

1. THE LOWER ALKYL ESTERS OF N-NAPHTHYL MALEAMIC ACID.